We have demonstrated the presence of specific receptor sites for 125I-insulin, glucagon and growth hormone on isolated rat hepatocytes. Subsequent to the initial binding interaction, a component of the cellularly bound hormone becomes associated with a very slowly dissociable hormone fraction. Cellular desensitization occurs concurrent with the accumulation of this slowly dissociable fraction on the target cell. Peptide hormone degradation also appears related to the generation of the slowly dissociable bound fraction. We propose to correlate loss of cellular sensitivity to applied hormone with the accumulation of slowly dissociable binding and peptide hormone degradation. Studies of a number of biologic endpoints will be directly related to the slowly dissociable binding fraction as well as with peptide hormone degradation. The slowly dissociable fraction of bound label will be extracted and characterized. Tentative localization of bound label will be effected using light microscopy autoradiography. This will permit definition of the relationship between hormonal degradation, which may require some degree of hormonal uptake by the cell, and the generation of the slowly dissociable binding fraction. It is expected that an understanding of the relationship between fractional receptor site occupancy resulting from the accumulation of a slowly dissociable binding fraction and cellular sensitivity will permit a fundamental insight into the basis of cell surface regulation in normal animals and the manner by which this may be changed in a number of pathophysiologic states, particularly in the diabetic.